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Ivermectin (Gonzalez)
Ivermectin (Gonzalez)
Jose Lenin Beltran Gonzalez MD1, Mario González Gámez MD1, Emanuel Antonio
Mendoza Enciso MD1, Ramiro Josue Esparza Maldonado MD1, Daniel Hernández Palacios
MD1, Samuel Dueñas Campos MD1, Itzel Ovalle Robles MD1, Mariana Jocelyn Macías
Guzmán MD1, Andrea Lucia García Díaz MD1, César Mauricio Gutiérrez Peña MD1,
Lucila Martinez Medina MD, MSc.2, Victor Antonio Monroy Colin MD2, Arreola Guerra
Corresponding Authors:
Medicine.
C.P. 20259
dr.jmag@gmail.com
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
C.P. 20259
mariogzg@hotmail.com
Abstract:
Background
In the search for active drugs against COVID-19, the indications of many have been
redirected. Ivermectin and Hydroxychloroquine are drugs that inhibit viral replication in
vitro and that have been used in several medical centers. Objectives: This clinical trial
and hospitalization criteria, but no severe respiratory failure. Patients were randomized to
one of three groups: Group1- hydroxychloroquine, 400 mg every 12 hours on the first day
and subsequently, 200 mg every 12 hours for 4 days, Group 2- ivermectin, 12 mg or 18 mg,
according to patient weight and, Group 3- placebo. At inclusion, blood samples for arterial
blood gases and biochemical markers associated with a poor prognosis were obtained. The
primary outcome was established as the duration of hospitalization until discharge due to
patient improvement, the total duration of hospitalization, and the safety outcomes were
either respiratory deterioration or death. Results. During the month of August, the
respiratory failure, so we ended the recruitment process and analyzed the data that was
available at the time. One hundred and six (106) patients with an average age of 53 yrs.
(±16.9) were included, with a greater proportion of males (n=66, 62.2 %). Seventy-two
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
percent (72%) (n= 76) had an associated comorbidity. Ninety percent (90 %) of patients
were discharged due to improvement (n=96). The average duration of hospitalization was 6
days (IQR, 3 – 10). No difference in hospitalization duration was found between the
deterioration, or deaths.
Introduction
On January 30, 2020, the World Health Organization declared a global health
emergency due to SARS-Cov-2 infections (COVID-19). (1) Since then, the outbreak has
spread to all continents and the number of confirmed cases continues to increase. To date,
Chloroquine and hydroxychloroquine belong to the aminoquinoline drug family, and are
broadly used as a result of their immunomodulatory and potentially antiviral effects and
their well-established safety profile. Since the development of the SARS-CoV public health
clinical presentations; however, they have not been shown to improve clinical outcomes.(3-
5)
In the search for active drugs against COVID-19, the indications of several drugs have
been redirected. One of the most studied is ivermectin, a macrolide obtained from
Streptomyces avermitilis. The FDA (Food and Drug Administration) authorized the use of
this antiparasitic agent in humans in 2008. Significant ivermectin in vitro antiviral effects
against SARS-Cov-2 have been recently reported, leading to the development of several
Methodology
secondary to SARS-CoV-2 infection and that fulfilled hospitalization criteria. These criteria
were defined according to the attending physician in the emergency department and
included the following parameters: severity of clinical presentation (determined with the
CURB-65 scoring system), need for supplemental oxygen, the presence of comorbidities
The patients included in the study had to fulfill the operational definition of a suspected
or confirmed COVID-19 case as well as the pneumonia ATS criteria.(1,8) The following
disease.
Patients were excluded if they required high oxygen volumes (face mask > 10 L/ min), if
they had predictors of a poor response to high-flow oxygen nasal prong therapy or if they
interval was measured with Bazett´s formula. Patients with an interval ≥ 500 ms were
randomized to ivermectin or placebo, while those with an interval < 500 ms were
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
the first day, followed by 200 mg every 12 hours for another 4 days. Due to the physical
administered as 2 tablets every 12 hours on the first day, followed by one tablet every 12
hours on the following 4 days. Blinding was assured with amber-colored vials. Each patient
had a vial for the initial dose in order to blind the ivermectin and a second vial for
subsequent doses. All patients received two vials, one with the initially prescribed dose and
a second one, with the indication to take two tablets 12 hours after the initial dose followed
complete blood count, blood chemistry, and prognostic markers such as fibrinogen, D-
partial thromboplastin times. If available, a high-resolution chest CT scan was also obtained
and if not, only a chest X-ray. The diagnostic probability of pneumonia due to SARS-CoV-
guidelines.(12,13)
During the last week of June and based on the RECOVERY trial, we initiated the
All included patients were under continuous cardiac monitoring and protocolized therapy
was withdrawn in patients that developed any arrhythmia or acute coronary syndrome.
breaths per minute, a required inspired oxygen fraction delivered by face mask or high-flow
nasal prongs of 60% or above, a PaO2/Fio2 ratio <200, or a ROX index at 12 hours <3.85
points.(9,15)
Hospital discharge was considered when the patient fulfilled the following criteria:
previous 72 hours, minimal oxygen requirements (nasal prongs at 1–2 liters per minute),
The main outcome was determined as the hospitalization duration until discharge due to
clinical improvement, the total duration of hospitalization, and the safety outcomes were
This study was conducted at the Hospital Centenario Miguel Hidalgo in the state of
Aguascalientes (Mexico), a tertiary care institution for the population lacking social
security.
The study protocol was approved by the Ethics Committee of the Hospital Centenario
Miguel Hidalgo on April 15, 2020, with the assigned number 2020-R-24. It was also
Statistical Analysis
Depending on the measurement level, descriptive statistics were used. The distribution
of continuous variables was determined with the Kolmogorov Smirnov test. Continuous
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
variables with a normal distribution are expressed in means and their standard deviation
while those with an abnormal distribution, as medians and their interquartile ranges.
analysis was evaluated with variance analysis (ANOVA) or the Kruskal Wallis test,
square or Fisher´s exact test, as needed. Survival analysis was performed for the outcomes
comparisons were obtained with the Log-rank test. A p value below 0.05 was considered
significant. Microsoft Excel 2013 and STATA version 11.1 software were used for
analysis.
if we want a reduction of 4 days of hospitalization, taking into account the mean differences
Results:
During the past month of August, we observed a very significant decrease in the
number of potential candidates that could be included in the study, since practically all
end recruitment and conduct an analysis with the data obtained as of August 15, 2020.
At the time of analysis, 108 patients had been recruited, two of which were eliminated
because they were transferred to another hospital. The patients´ average age was 53 years
(±16.9), and there was a greater proportion of males (n=66, 62.2 %). Comorbidities were
present in 72% of cases (n= 76). Type 2 diabetes mellitus and systemic arterial
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
hypertension were the most frequent (33.9 and 32.1 %). Mean body weight was 82.3 kg
RADS 5, while 24 patients had an image with a low probability of SARS-CoV-2 infection
according to that scoring system, but they had a diagnostically compatible clinical
The ratio between the Arterial Oxygen pressure (PaO2) and the Inspired Oxygen fraction
(PaO2/FiO2) was greater than 200 mmHg in 64 patients; 42 patients had severe respiratory
in 96 % and CURB-65 ≥2 points in 34.9 %. The score in severity scales was not different
between-groups (Table 4)
During hospitalization, 52.3% of patients received some form of antibiotic, 92.2% were on
Outcomes
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
The average duration of hospitalization was 6 days (IQR 3 – 10). Ninety percent (90 %)
of patients were discharged after clinical improvement (n=96). Twenty-three (23) patients
result of respiratory failure, and three with sepsis due to bacterial coinfection. No
differences in outcome were detected between the treatment groups (Table 6). The time
until death or respiratory deterioration was also not different between groups (figure 1).
Discussion
In this study of non-critically ill patients with pneumonia secondary to COVID-19 and
In the first weeks of the COVID-19 pandemic, there was in vitro evidence on the efficacy
supporting its use. This led various medical centers and health systems to recommend it
based on compassionate use. This strategy fostered panic purchases and prescriptions
leading to drug shortages for patients with well-established indications. As months went by,
its inefficacy was suspected and reports from the SOLIDARITY study finally proved its
therapeutic futility in decreasing mortality, and patient recruitment was stopped.(16) Our
Although adverse events have been reported with the use of hydroxychloroquine,
As with hydroxychloroquine, ivermectin was proposed in the early phases of the pandemic,
as treatment and even prophylaxis of SARS-CoV-2 infection. It has mainly been used in
COVID-19; some health ministries have even modified their treatment policies
As in the case of hydroxychloroquine, evidence in favor of ivermectin use was the result
those findings is the fact that the in vitro efficacy of ivermectin in decreasing the viral load
unplausible proposal in the clinical setting.(19) To our knowledge, our study is the first
The characteristics of patients enrolled in our study differ from those in series published
in China and some European countries early on since our population has a greater incidence
They have a greater load of comorbid disease thus impacting clinical results. As in the
initial case series, systemic arterial hypertension and type 2 diabetes mellitus were the main
entities compromising the patients´ course and fostering their development of respiratory
The main strength of this clinical trial is the fact that it represents the response of a
patients were offered two therapeutic alternatives that at the beginning of the pandemic
appeared to be potentially effective. Although the patient number is not sufficient to reach
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
categorical conclusions, the study´s design certainly suggests that both drugs are
ineffective. We hope it will contribute to meta-analyses that may yield more robust
conclusions.
The study´s main weakness is the limited number of patients per group; also, among the
tests became negative, due to the lack of reactants and the minimal usefulness of proving its
COVID-19, the use of hydroxychloroquine or ivermectin did not decrease the number of
Conflict of interest
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medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
Footnotes
Table 1.- Population characteristics. SAH: Systemic Arterial Hypertension, CKD: Chronic Kidney
Disease, COPD: Chronic Obstructive Pulmonary Disease, BMI: Body Mass Index
Table 3.- Biochemical and gasometric markers. O2Sat: Oxygen saturation, PaO2/FiO2: Index
of Oxygen arterial pressure / inspired oxygen fraction, PCO2: Carbon dioxide pressure, Hb:
Table 6. Outcomes
(n=33)
Age, m (±SD) 53.8 (16.9) 48.9 (15.3) 56 (16.5) 53.8 (16.9) 0.15
(%)
BMI, m (±DE) 29.6 (6.6) 30.3 (6.3) 29.2 (7) 29.4 (6.6) 0.55
Table 1.- Population characteristics. SAH: Systemic Arterial Hypertension, CKD: Chronic Kidney
Disease, COPD: Chronic Obstructive Pulmonary Disease, BMI: Body Mass Index
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
(n=28)
(n=33)
PaO2/FiO2, m (±DE) 223 (103) 224 (116) 245 (107) 201 (82) 0.17
PCO2, m (±SD) 29 (7.5) 26.3 (7.9) 30.4 (7.2) 30.3 (6.8) 0.09
Lactate, m (±SD) 1.41 (0.6) 1.45 (0.7) 1.2 (0.6) 1.5 (0.6) 0.31
Hb, m (±SD) 13.5 (2.9) 13.6 (3) 13.1 (3) 13.7 (2.8) 0.63
Neutrophils, m (±SD) 8 (4.1) 7.7 (3.4) 8.4 (4.8) 7.8 (4.1) 0.82
Lymphocytes, m (±SD) 1.3 (0.6) 1.3 (0.54) 1.2 (0.6) 1.4 (0.7) 0.40
Platelets, m (±SD) 254 (104) 250 (91) 261 (100) 251 (119) 0.90
Creatinine, m (±SD) 1.48 (2.8) 0.95 (0.7) 1.6 (3.3) 1.8 (3.4) 0.81
LDH, m (±SD) 394 (158) 394 (189) 369 (123) 394 (158) 0.19
D-Dimer, m (±SD) 1618 (1442) 1593 (1845) 1872 (1137) 1380 (1268) 0.01
Fibrinogen, m (±SD) 441 (247) 439 (249) 473 (250) 413 (244) 0.53
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
CRP, m (±SD) 117 (136) 171 (122) 187 (126) 172 (158) 0.67
Ferritin, m (±SD) 721 (927) 669 (667) 902 (1125) 592 (910) 0.35
D Bilirubin, m (±SD) 0.64 (1.6) 0.91 (2.9) 0.53 (0.5) 0.5 (0.6) 0.56
Troponin, m (±SD) 0.05 (0.2) 0.1 (0.3) 0.03 (0.08) 0.02 (0.02) 0.18
Table 3.- Biochemical and gasometric markers. O2Sat: Oxygen saturation, PaO2/FiO2: Index
of Oxygen arterial pressure / inspired oxygen fraction, PCO2: Carbon dioxide pressure, Hb:
Hemoglobin, LDH: Lactic Dehydrogenase, CRP: C reactive protein
106) (n=33)
SOFA, m (SD) 3.3 (1.6) 3.1 (1.5) 2.9 (1.5) 3.8 (1.7) 0.05
APACHE II, m8 -15 11.2 (4) 11.1 (3.8) 10.6 (3.7) 11.9 (4.4) 0.38
CURB65, m (±SD) 1.08 (1.03) 0.9 (0.9) 1.1 (1) 1.1 (1.1) 0.77
(n=33)
106)
Hospitalization,
med (IQR)
discharge, n
(%)
without
respiratory
deterioration
or death, n (%)
deterioration
or death, n (%)
medRxiv preprint doi: https://doi.org/10.1101/2021.02.18.21252037; this version posted February 23, 2021. The copyright holder for this preprint
(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY 4.0 International license .
Table 6. Outcomes